This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Age-related cataract is a major cause of blindness worldwide. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. Homozygous deletion of the EPHA2 gene in two independent strains of mice developed progressive cortical cataract. EPHA2 is highly expressed in both human and mouse lens fiber cells and its expression level decreases with aging in mice. The orthologous gene resides on human 1p36 that was previously reported as showing linkage with age-related cortical cataract in a population-based cohort. We sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln in the protein kinase domain which significantly alters EPHA2 functions. Common variants in EPHA2 also showed significant association, and rs6678616 was the most significant in meta-analysis. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with increasing age.